Study Confirms that Protease Inhibitor Cocktail Can Delay HIV Disease Progression and Death

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A NIAID-funded study has shown that the combination of a protease inhibitor plus two nucleoside analogue reverse transcriptase inhibitors (RTIs) is significantly more effective in reducing the occurrence of AIDS-defining illnesses or death in patients with advanced HIV disease than two RTIs alone. The study, known as AIDS Clinical Trials Group (ACTG) 320, was designed to determine the efficacy and safety of the protease inhibitor indinavir when given in combination with zidovudine (ZDV) and lamivudine (3TC), as compared to ZDV plus 3TC.

Recent data showing the dramatic effectiveness of protease inhibitors in lowering viral burden have led to their widespread use in combination with other AIDS drugs. "The results of ACTG 320 confirm the importance of including protease inhibitors in treatment strategies for patients with advanced HIV disease," says Anthony S. Fauci, M.D., NIAID director. "Significantly, the current study provides additional evidence that combination approaches using protease inhibitors can reduce the risk of death."

An independent data and safety monitoring board recommended early termination of enrollment and closure of the study after preliminary results showed that the three-drug regimen significantly reduced disease progression and death.

"The further, significant reduction in disease progression conferred by indinavir when given as part of a three-drug combination illustrates the rapid progress that the field of HIV therapeutics has made in the last two years and suggests that further benefits can be achieved with regimens of ever-increasing potency," commented Scott Hammer, M.D., of Beth Israel Deaconess Medical Center in Boston and protocol chair of ACTG 320.

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Volunteers in the study had CD4+ T cell counts below 200 per cubic millimeter (mm3) of blood at study entry and had taken ZDV for at least three months, but had received less than one week of 3TC and no protease inhibitors. They were randomized to receive either the combination of ZDV (600 mg/day), 3TC (300 mg/day) and indinavir (2400 mg/day), or ZDV plus 3TC plus placebo. Participants intolerant to ZDV could use stavudine (d4T), and those developing toxicities or experiencing mild disease progression were allowed to change to other approved nucleoside analogues. The majority of participants received ZDV and 3TC for the duration of the study.

A total of 1,156 HIV-infected volunteers participated in ACTG 320. Participants were enrolled at 33 ACTG sites, and at seven sites of the National Hemophilia Foundation. They were followed for a median of 38 weeks, with some patients being followed for up to one year.

Among patients receiving triple combination therapy, AIDS-defining illnesses, including opportunistic infections and cancers, and deaths were decreased by approximately half. Sixty-three instances of disease progression (including AIDS-defining illnesses and deaths) occurred in volunteers on the ZDV/3TC arm versus 33 in volunteers on the triple combination arm.

The benefit was statistically significant for the subset of patients with CD4+ T cell counts less than 50/mm3, and there was a similar trend for patients with CD4 counts between 50 cells/mm3 and 200 cells/mm3. There were 18 deaths in the double therapy arm versus eight deaths in the triple therapy arm. Further studies are needed to understand the long-term impact of this triple combination. Sub-studies of ACTG 320 are currently being analyzed, including a study of how the various treatments affect the amount of virus in patients' blood and to characterize the development of drug resistance in the different treatment arms.

The drugs used in this study were provided by their manufacturers: Merck & Co., Inc. (indinavir/ Crixivan®), Glaxo Wellcome, Inc. (ZDV/Retrovir® and 3TC/Epivir®), and Bristol-Myers Squibb Co. (d4T/Zerit® and ddI/Videx®). Merck also provided financial support for the study.

-- Pat Randall

A note from TheBody.com: The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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